The crystallins are the basic structural elements of the ocular lens. These globular, structural proteins are evolutionarily conservative proteins with structures uniquely suited to their functional role, ie, to form highly organized and densely packed protein matrices which are optically transparent. Our studies are oriented toward elucidation of the mechanisms of cataract development and the role of changes either in the structure or the composition of the crystallins in opacification of the lens. With respect to structural modifications to crystallins, we are particularly interested in the modifications induced by oxidative stress since the lens is exposed in vivo to an unusual level of such stress. We have previously investigated the potential effects of the high concentration of hydrogen peroxide in the aqueous humor on intact lenses in organ culture, finding that hydrogen peroxide is toxic whereas stronger but short-lived oxidants (free radicals) derived from it show little toxicity when produced in the fluids surrounding the lens. In model systems we have now shown that when generated intracellularly the reverse is true. Hydrogen peroxide itself causes little damage, but upon conversion of hydroxyl radicals or related species the crystallins are rapidly oxidized. Thus not only the oxidizing species, but the location in which it is generated is critical in determining its potential for producing lens damage. We have recently found that zeta-crystallin, a lens protein unique to guinea pigs which we discovered and partially characterized, is absent or present in sharply reduced amounts in the lenses of guinea pigs with hereditary congenital nuclear cataracts. This finding gives us an ideal opportunity to investigate in an animal model system the effect of a major change in crystallin composition.